Eslicarbazepine acetate, (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide, is a new drug currently being developed which is useful for the treatment of various conditions, such as, for example, epilepsy and affective brain disorders, as well as pain conditions and nervous function alterations in degenerative and post-ischemic diseases. Although chemically related to carbamazepine and oxcarbazepine, eslicarbazepine acetate is believed to avoid the production of certain toxic metabolites (such as, for example, epoxides) and to avoid the unnecessary production of enantiomers or diastereoisomers of metabolites and conjugates, without losing pharmacological activity (Almeida et al., 2005a; Almeida et al., 2005b; Almeida et al., 2002; Almeida et al., 2003; Almeida et al., 2004; Benes et al., 1999; Bialer et al., 2004; Soares-da-Silva, 2004). Unlike oxcarbazepine, eslicarbazepine acetate is almost entirely metabolized to the active metabolite eslicarbazepine (Almeida et al., 2005a; Almeida et al., 2005b).
Throughout the specification, the term “pharmacoresistant”, and variations thereon, will be understood to relate to a condition where the patient is not responsive to pharmaceutical treatment at all;
the term “refractory” will be understood to relate to a condition wherein the patient becomes progressively less responsive to their medication and, in the case of epilepsy, suffers from an increasing number of seizures; and
the term “intractable”, and variations thereon, will be understood to signify difficult-to-treat or treatment(drug)-resistant and thus encompasses both pharmacoresistant and refractory conditions.
Resistance to pharmacological therapy (pharmacoresistance) is one of the major problems in the treatment of epilepsy (Löscher et al., 2004). Approximately one third of all epilepsy patients do not become seizure free, despite treatment with two or more antiepileptic drugs (AEDs) at a maximal tolerated dose. This intractability is even higher (50-70%) in patients with temporal lobe epilepsy (Kwan et al., 2000; Mohanraj et al., 2005; Schmidt et al., 2005; Stephen et al., 2006). Although the causes and mechanisms underlying pharmacoresistance are not fully understood, drug-efflux transporters of the adenosine triphosphate (ATP)-binding cassette (ABC) family (multidrug transporters) may play an important role. P-glycoprotein (P-gp or ABCB1 or MDR1) is the most extensively studied multidrug transporter. In fact, P-gp transports a variety of xenobiotics, including commonly used AEDs (Potschka et al., 2002; Potschka et al., 2001a; Potschka et al., 2001b; Rizzi et al., 2002; Sills et al., 2002).
In fact, a current popular hypothesis is that overexpression of drug efflux (“multidrug”) transporters at the brain capillary endothelium induced by repetitive seizure activities lowers AED concentration in brain interstitial fluid and contributes to drug resistance (Kwan et al., 2005; Löscher et al., 2005a; Löscher et al., 2005b; Schmidt et al., 2005). Several studies have shown that such drug efflux transporters, including P-glycoprotein (P-gp or MDR1) and members of the multidrug resistance protein (MRP) family, are overexpressed in surgically resected brain tissue from patients with medically intractable epilepsy (Kwan et al., 2005; Löscher et al., 2005a; Löscher et al., 2005b; Schmidt et al., 2005). Furthermore, in epileptogenic brain tissue from patients with pharmacoresistant epilepsy, an overexpression of several multidrug transporters, including P-glycoprotein (P-gp) and members of the multidrug resistance protein (MRP) family such as MRP1 and MRP2 has been reported (Aronica et al., 2003; Dombrowski et al., 2001; Sisodiya et al., 2002; Tishler et al., 1995). Overexpression was found both in brain capillary endothelial cells that form the blood—brain barrier (BBB) and in astrocytes and astrocyte processes that ensheath the endothelial cells and contribute to BBB function. In human refractory epileptic brain tissue (Aronica et al., 2003; Aronica et al., 2004; Marchi et al., 2004; Sisodiya et al., 2002; Tishler et al., 1995), as well as in the epileptic rat brain (van Vliet et al., 2004; Volk et al., 2004a; Volk et al., 2004b), P-gp is overexpressed in endothelial cells, neurons, and glial cells. P-gp overexpression, particularly in endothelial cells, may lead to increased extrusion of drugs from the brain to the blood, preventing the attainment of appropriate AED concentrations at therapeutic targets. Because multidrug transporters such as P-gp and MRPs accept a wide range of drugs as substrates, overexpression of such efflux transporters in the BBB would be one likely explanation for resistance to various AEDs in a patient with intractable epilepsy (Kwan et al., 2005; Löscher et al., 2005a; Löscher et al., 2005b; Schmidt et al., 2005).
The consequences of uncontrolled epilepsy can be severe, and include shortened lifespan, bodily injury, neuropsychological and psychiatric impairment, and social disability (Sperling, 2004). Most patients with refractory epilepsy are resistant to several, if not all, AEDs, despite the fact that these drugs act by different mechanisms (Kwan et al., 2000; Sisodiya, 2003). This multidrug type of resistance argues against epilepsy-induced alterations in specific drug targets as the main cause of pharmacoresistant epilepsy, pointing instead to nonspecific and possibly adaptive mechanisms (Sisodiya, 2003). Epilepsy was the first CNS disorder for which drug resistance was associated with enhanced expression of multidrug transporters in the brain (Tishler et al., 1995). The expression of multidrug transporters in the astroglial end-feet covering the blood vessels that are found in epileptogenic brain tissue might represent a ‘second barrier’ under these conditions (Abbott, 2002; Sisodiya et al., 2002). Several widely used AEDs, which have been made lipophilic to allow them to penetrate the brain, are substrates for P-gp or MRPs in the BBB (Potschka et al., 2002; Potschka et al., 2001a; Potschka et al., 2003; Potschka et al., 2001b; Rizzi et al., 2002; Schinkel et al., 1996; Sills et al., 2002; Tishler et al., 1995). As a result, the uptake of these drugs by the brain can be increased by knocking out or blocking P-gp. The overexpression of these transporters in epileptogenic tissue is likely, therefore, to reduce the amount of drug that reaches the epileptic neurons. This is one plausible explanation for multidrug resistance in epilepsy (Sisodiya, 2003).
Although the multidrug transporter hypothesis of intractable epilepsy is biologically plausible, it has not been proven (Löscher et al., 2004; Sisodiya, 2003). Despite the fact that high P-gp expression has been shown in epileptogenic brain tissue from patients with intractable epilepsy, adequate controls are lacking, as it is impossible to compare this tissue directly with tissue from patients who respond well to AED treatment (because these patients do not need to undergo surgical resection of epileptogenic foci). Consequently, it is not clear whether the increased P-gp expression in patients with drug-resistant epilepsy is a cause of pharmacoresistance or just a result of uncontrolled seizures—or an epiphenomenon that occurs in epileptic brain tissue irrespective of drug response. For direct proof-of-principle, it should be established whether P-gp inhibitors counteract multidrug resistance in epilepsy. In line with this suggestion, Summers et al. (Summers et al., 2004) recently reported that combined treatment with verapamil and AEDs greatly improved overall seizure control and subjective quality of life in a patient with intractable epilepsy. Verapamil is a calcium channel blocker that is transported by P-gp and competitively blocks the transport of other substrates by P-gp (Schinkel et al., 2003). Because of its efficient efflux transport by P-gp at the BBB, verapamil itself does not penetrate into the brain (Kortekaas et al., 2005), so the improved seizure control observed both experimentally and clinically in response to co-administration of verapamil and AEDs is not secondary to the calcium channel-blocking effect of verapamil. Following the promising clinical results of combined treatment with verapamil and AEDs (Summers et al., 2004), Summers et al. went on to test combinations of AEDs and verapamil in other patients with drug-resistant epilepsy, again with a favourable outcome (for details see (Löscher et al., 2005a)).
Oxcarbazepine has been used either in monotherapy or in adjunctive therapy in patients with partial-onset seizures with or without secondary generalization (May et al., 2003; Schmidt et al., 2001; Shorvon, 2000; Tartara et al., 1993). Oxcarbazepine undergoes rapid 10-keto reduction to a mixture of S-licarbazepine and R-licarbazepine the racemic mixture if which is usually referred as licarbazepine (10-hydroxy-10,11-dihydrocarbazepine, 10-OHCBZ, or MHD) (Faigle et al., 1990; Feldmann et al., 1978; Feldmann et al., 1981; Flesch et al., 1992; Schutz et al., 1986; Volosov et al., 1999).
Recently, licarbazepine (10-OHCBZ) was suggested not to cross the blood-brain barrier by simple diffusion, namely being a substrate of P-gp. In fact, the level of expression of MDR1 was found to be inversely correlated with 10-OHCBZ concentration in the epileptic tissue (Marchi et al., 2005). It was concluded that P-gp may play a role in the resistance to oxcarbazepine by determining the attainment of insufficient concentrations of its active metabolite at neuronal targets (Marchi et al., 2005). In the rat, which does not convert oxcarbazepine to licarbazepine (10-OHCBZ), co-administration of the P-gp inhibitor verapamil significantly potentiated the anticonvulsant activity of oxcarbazepine in the pilocarpine seizure model (Clinckers et al., 2005). However, it remains to be determined whether P-gp or MRPs are endowed with identical affinity for S-licarbazepine and R-licarbazepine.